Promising Outcomes of Original Grant:
The goal of the previous project was to establish iPS-derived neurons from patients with PINK1- and Parkin-linked familial forms of PD. We used the latest technological advances, in collaboration with the PD iPS Consortium, to ensure consistent and reliable neuronal differentiation of these iPS lines, followed by the phenotypic characterization of the differentiated neurons. Mitochondrial dysfunction was uncovered in Parkin and PINK1 iPS-derived neurons under basal conditions and following treatments with mitochondrial stressors. In order to validate that these phenotypes were caused by the genetic mutations, we employed therapeutic strategies to rescue the mitochondrial abnormalities.
Objectives for Supplemental Investigation:
Our overall hypothesis in this application is that impairment of mitochondrial and lysosomal function in vulnerable neurons plays a key role in the pathogenesis of PD and that restoration of mitochondrial and/or lysosomal function will result in neuroprotection. We previously established a mechanistic link between a rare lysosomal storage disease, Gaucher disease (GD) and PD, suggesting that lysosomal dysfunction plays a key role in the development of a-syn aggregates and neurodegeneration. Here, we plan to examine the convergence of these important pathways in PD, a-synuclein accumulation, lysosomal and mitochondrial dysfunction.
Importance of this Research for the Development of a New PD Therapy:
There is an imperative to examine appropriate human derived cell models to validate findings in other systems and to investigate novel disease mechanisms. This project will establish whether human dopaminergic iPS neurons develop discernable phenotypes that are amenable to therapeutic rescue. The study will demonstrates whether it is possible to employ patient-derived, disease-specific cell models as tools to investigate and validate pathogenic mechanisms of PD, and suggests that this powerful approach will be very useful for future development for novel therapies.